tbuckley/cabot-search huggingface dataset:
A phase II study of alectinib in combination with bevacizumab as first-line treatment in advanced NSCLC with confirmed ALK fusion: ALEK-B trial.
Authors: Oscar Gerardo Arrieta, Luis Antonio Lara Mejía, Luis Antonio Cabrera, Maritza Ramos, David Jose Heredia, Graciela Cruz-Rico, Miguel Angel Salinas, Daniela Cardenas Fernández, Zyanya Lucía Zatarain-Barron, Andres Felipe Cardona Zorrilla, Jordi Remon Masip, Rafael Rosell
Journal: Journal of Clinical Oncology (2022)

9074 Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31 st , 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no &gt; G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.
Maturation of induced pluripotent stem cell-derived cardiomyocytes and its therapeutic effect on myocardial infarction in mouse
Authors: Peng Wu, Xiyalatu Sai, Zhetao Li, Xing Ye, Li Jin, Guihuan Liu, Ge Li, Pingzhen Yang, Mingyi Zhao, Shuoji Zhu, Nanbo Liu, Ping Zhu
Journal: Bioactive Materials (2022)

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have an irreplaceable role in the treatment of myocardial infarction (MI), which can be injected into the transplanted area with new cardiomyocytes (Cardiomyocytes, CMs), and improve myocardial function. However, the immaturity of the structure and function of iPSC-CMs is the main bottleneck at present. Since collagen participates in the formation of extracellular matrix (ECM), we synthesized nano colloidal gelatin (Gel) with collagen as the main component, and confirmed that the biomaterial has good biocompatibility and is suitable for cellular in vitro growth. Subsequently, we combined the PI3K/AKT/mTOR pathway inhibitor BEZ-235 with Gel and found that the two combined increased the sarcomere length and action potential amplitude (APA) of iPSC-CMs, and improved the Ca2+ processing ability, the maturation of mitochondrial morphological structure and metabolic function. Not only that, Gel can also prolong the retention rate of iPSC-CMs in the myocardium and increase the expression of Cx43 and angiogenesis in the transplanted area of mature iPSC-CMs, which also provides a reliable basis for the subsequent treatment of mature iPSC-CMs.
PSMA-flare after ADT evaluated with 18F-PSMA-1007 PET/CT in hormone-sensitive metastatic prostate cancer: Possible predictor of tumour aggressiveness?
Authors: S. Malaspina, O. Ettala, T. Tolvanen, S. Forsback, P.J. Boström, J. Kemppainen
Journal: European Urology (2022)
IMG-17. Advanced MRI On The Cellular and Vascular Phenotype of Mouse Ependymoma Models and Chemo-Radiation Treatment Response
Authors: Natalie Serkova, Jane Manalo, Jenna Steiner, Andrea Griesinger, Angela Pierce, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract Ependymoma (EPN) is an aggressive pediatric brain tumor, for which the benefits of chemotherapy in pediatric patients have not been defined. EPN treated with surgery and radiation recur in 23-66% of patients. Our group has previously established aggressive behaviors of EPN, including high tumor cellularity, cytological anaplasia, high mitotic index, tumor necrosis, and the presence of inflammatory cells such as M2-type myeloid cells. Here we report on an advanced 9.4 Tesla MRI protocol for characterizing the cellular and vascular phenotype and treatment response to chemo-radiation therapy (CRT) in an orthotopic mouse model of patient derived xenografts (PDX) of pediatric EPN . Female severely immune deficient (SCID) mice were used for intracranial inoculation of disaggregated tumors from pediatric EPN patients (n=22). High-resolution T2w-MRI was able to detect cerebellar microlesions as small as 0.2 mm diameter; the median tumor volumes at the baseline were 21±12 mm3. Using diffusion-weighted based cell-size imaging, iron-oxide based vessel-size imaging and quantitative T2-maps, the EPN-specific phenotype was characterized by an increased cell size (S=14 microns), increased vessel density index (Q=0.54), and low ADC values (0.63x10-3). Once the intracranial tumors reached at least 5 mm3, animals were treated with CRT (10 Gy radiation plus 30 mg/kg 5-fluorouracil, n=6). CRT resulted in a tumor shrinkage, tumor necrosis with decreased cell sizes and increased ADC values, and a dramatic vascular-inflammatory response (decreased Q and DT2 values with the injection of iron oxide nanoparticles as macrophage-specific contrast). In summary, orthotopically implanted PDX EPN in mice closely mimic histological features, anatomical location and radiological features of the primary tumors. A significant decrease in vessel size density and an increase in inflammatory cells were seen as soon as 2 days after CRT. The late response (2 weeks post CRT) is characterized by decreased cellularity, cell size, and tumor volumes.
Accuracy Difference of Noninvasive Blood Pressure Measurements by Sex and Height
Authors: Yasmine Abbaoui, Catherine Fortier, Louis-Charles Desbiens, Cédric Kowalski, Florence Lamarche, Annie-Claire Nadeau-Fredette, François Madore, Mohsen Agharazii, Rémi Goupil
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Women are at higher risk of cardiovascular events than men with similar blood pressure (BP). Whether this discrepancy in risk is associated with the accuracy of brachial cuff BP measurements is unknown. <h3>Objectives</h3> To examine the difference in brachial cuff BP accuracy in men and women compared with invasively measured aortic BP and to evaluate whether noninvasive central BP estimation varies with sex. <h3>Design, Setting, and Participants</h3> This cross-sectional study enrolled 500 participants without severe aortic stenosis or atrial fibrillation from January 1 to December 31, 2019, who were undergoing nonurgent coronary angiography at a tertiary care academic hospital. <h3>Exposures</h3> Simultaneous measurements of invasive aortic BP and noninvasive BP. <h3>Main Outcomes and Measures</h3> Sex differences in accuracy were determined by calculating the mean difference between the noninvasive measurements (brachial and noninvasive central BP) and the invasive aortic BP (reference). Linear regression and mediation analyses were performed to identify mediators between sex and brachial cuff accuracy. <h3>Results</h3> This study included 500 participants (145 female [29%] and 355 male [71%]; 471 [94%] White; mean [SD] age, 66 [10] years). Baseline characteristics were similar for both sexes apart from body habitus. Despite similar brachial cuff systolic BP (SBP) (mean [SD], 124.5 [17.7] mm Hg in women vs 124.4 [16.4] in men;<i>P</i> = .97), invasive aortic SBP was higher in women (mean [SD], 130.9 [21.7] in women vs 124.7 [20.1] mm Hg in men;<i>P</i> &lt; .001). The brachial cuff was relatively accurate compared with invasive aortic SBP estimation in men (mean [SD] difference, −0.3 [11.7] mm Hg) but not in women (mean [SD] difference, −6.5 [12.1] mm Hg). Noninvasive central SBP (calibrated for mean and diastolic BP) was more accurate in women (mean [SD] difference, 0.6 [15.3] mm Hg) than in men (mean [SD] difference, 8.3 [14.2] mm Hg). This association of sex with accuracy was mostly mediated by height (3.4 mm Hg; 95% CI, 1.1-5.6 mm Hg; 55% mediation). <h3>Conclusions and Relevance</h3> In this cross-sectional study, women had higher true aortic SBP than men with similar brachial cuff SBP, an association that was mostly mediated by a shorter stature. This difference in BP measurement may lead to unrecognized undertreatment of women and could partly explain why women are at greater risk for cardiovascular diseases for a given brachial cuff BP than men. These findings may justify the need to study sex-specific BP targets or integration of sex-specific parameters in BP estimation algorithms.
DIPG-03. Therapeutic targeting of purine biosynthesis in DIPG
Authors: Ian Mersich, Biplab Dasgupta
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Currently there are no targeted therapies that significantly improve overall survival in patients with this disease. To this end, we are developing a metabolic profile for this disease by integrating metabolomics and gene expression data from cell lines derived from DIPG patient tumors. Our long-term goal is to significantly improve the overall survival of children with DIPG by identifying novel therapeutic targets. Central to this goal is our investigation into dysregulated purine metabolism in these tumors. We’ve integrated gene expression and metabolomic datasets for DIPG cells and identified a potential therapeutic target in the de novo purine biosynthesis (DNPB) pathway. Genetic knockout experiments confirmed that DIPG cells require the last enzyme in the DNPB pathway, ATIC, for survival. Furthermore, we have identified a compound that disrupts ATIC homo-dimerization, which is required for ATIC catalytic activity. Our preliminary data demonstrates this compound may offer clinical benefits over traditional antifolates that target this same pathway; however, the mechanism leading to selective cytotoxicity was unclear. Antifolates such as methotrexate competitively inhibit folate binding sites in multiple enzymes within this pathway; however, there are known mechanisms of resistance to these drugs. We show that the ATIC dimerization inhibitor differs from the antifolates by disrupting a multi-enzyme complex known as the purinosome, which requires intact, functional ATIC for assembly. Furthermore, targeting ATIC through genetic and pharmacological inhibition in vivo has extended survival in our PDX mouse model of DIPG.
<i>TP53</i> Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study
Authors: Kristina W. Thiel, Eric J. Devor, Virginia L. Filiaci, David Mutch, Katherine Moxley, Angeles Alvarez Secord, Krishnansu S. Tewari, Megan E. McDonald, Cara Mathews, Casey Cosgrove, Summer Dewdney, Carol Aghajanian, Megan I. Samuelson, Heather A. Lankes, Robert A. Soslow, Kimberly K. Leslie
Journal: Journal of Clinical Oncology (2022)

The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome.From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm.In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed.IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.
Evaluating anticancer agents on 3D bioprinted organoid tumors (BOT) to reduce cost and accelerate therapeutic discovery.
Authors: Zeelu H. Patel, Areesha A. Charania, Zeenia Punjani, Heli K. Patel, Mary Kathryn Sewell-Loftin, Mansoor N. Saleh, Karim I. Budhwani
Journal: Journal of Clinical Oncology (2022)

e13500 Background: Despite recent advances in therapeutics, cancer remains the second leading cause of death worldwide. Next generation cancer models hold the promise of breaking this stranglehold. However, extracting adequate tissue for precision and personalized medicine ex vivo models can be difficult depending on tumor type and tissue site. Mechanisms to expand tissue include patient derived xenografts and patient derived organoids. The former imposes a large time window to establish while the latter is constrained in space by sizescales. Advances in 3D bioprinting have improved the ability to reproduce the three-dimensionality and heterogeneity of the tumor microenvironment. Here we present a novel mechanism to address space and time constrains with 3D bioprinted organoid tumors (BOT) that mimic core needle biopsy tissue to reduce both cost and time to market for novel therapeutics making effective cancer therapy more accessible and equitable. The aim of this study is to produce and use BOT core biopsy tissue in ex vivo precision and personalized medicine applications. Methods: Bioinks prepared with MDA-MB-231 cells, fibrinogen, and thrombin will be deposited layer-by-layer on microporous substrate, in various geometrical configurations, and cured in stages to allow cells and matrix to self-assemble with limited degrees of freedom. Bioprinted organoid tissue will be fully cured to mimic patient biopsy cores, which will then be loaded in ex vivo bioreactors to evaluate sensitivity and resistance of small molecule and biologics. Results: Tissue 3D microarchitecture was validated using high-content fluorescence imaging and custom image processing applications. Diffusion of mock agents, small molecule, and nucleic acid stains was measured 200 mm deep in tissue. Differential activity in spatially distinct regions of intact BOT cores was quantified using advanced image processing modules. Conclusions: Patient derived BOT cores could be used both as a predictive model to screen drugs on an individualized basis and to uncover new therapeutic targets to improve efficacy and reduce toxicity. Due to their ability to replicate the physical and biochemical characteristics of a tumor and its microenvironment, BOT based precision and personalized medicine models can provide more accurate data on drug efficacy and toxicology when compared to in vitro cancer models.
Prevalence of ocular comorbidities in patients with multiple myeloma: An analysis of U.S. claims data.
Authors: Sikander Ailawadhi, Qiufei Ma, Jessica J. Jalbert, Mo Zhou, Zheng-Yi Zhou, Nathaniel Downes, Allison Briggs, Lei Chi, Christian Hampp, Xue Song, Irene Noguera-Troise, Jonathan Weyne, Glenn Scott Kroog, Karen Rodriguez-Lorenc
Journal: Journal of Clinical Oncology (2022)

8038 Background: Multiple myeloma (MM) predominantly affects older patients (pts) (median age at diagnosis 69 yrs) in whom comorbidities must be considered to manage the disease appropriately. Some anti-MM therapies can be associated with ocular toxicities and require careful attention when used among pts with pre-existing ocular comorbidities (OC). In 2018, 41% of Medicare enrollees had OC. Despite the potential implication on treatment decisions, information on pre-existing OC (e.g., disorders of lens, glaucoma) in MM pts is limited. This study aims to describe the prevalence of OCs among real-world pts with MM in 2011-2020 in the US. Methods: Adults with newly diagnosed MM (NDMM) with or without treatment, with 1L systemic therapy, and with relapsed/refractory MM (RRMM) who received up to 4 lines of systemic therapies (LOT) for MM were identified in the IQVIA PharMetrics Plus data. The index date was the date of initial MM diagnosis or a LOT initiation date. The prevalence of OC in each group was defined as the presence of any OC ICD 9/10 diagnosis codes in the 12 months prior to the index date. OCs (e.g., disorders of conjunctiva, lens, choroid, retina, glaucoma) were considered a potentially MM-related disease manifestation or MM treatment-related toxicity based on published literature and clinical expert opinion. Results: The median age at initial MM diagnosis was 64 yrs overall (N=49,814), and 63 yrs among treated pts (N=22,963). The median age was 63 yrs at 1L initiation and 64 yrs at 2L, 3L, and 4L initiation. The prevalence of OC at initial MM diagnosis was 39.0% overall and 35.2% among treated pts (Table). The OC prevalence was 35.8% prior to 1L initiation and higher in RRMM pts (42.1%, 44.9%, and 45.7% prior to 2L, 3L, and 4L initiation, respectively). This trend was observed across all OC categories, among MM-related OCs, and across all age groups. The prevalence of OC by MM stage was stable over the years. Conclusions: Approximately 40% of NDMM pts have a pre-existing OC, and the prevalence increases with the number of LOT in RRMM. While some OC may be due to aging, the impact of OC on treatment decisions for MM should be explored. [Table: see text]
Improved response prediction to immune checkpoint inhibition by combining TMB and WGS-based genomic features in NSCLC.
Authors: Klaudia Pacewicz, Andrzej Kraszewski, Michal Medzin, Paulina Nawrocka-Muszynska, Mateusz Sypniewski, Dawid Sielski, Paweł Sztromwasser, Weronika Majer-Burman, Maciej Piernik, Alicja Wozna, Paweł Zawadzki
Journal: Journal of Clinical Oncology (2022)

e21077 Background: The appearance of immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in advanced NSCLC. The clinical efficacy and indications for ICIs are currently estimated using the immunohistochemistry (IHC) profile of programmed death-ligand 1 (PD-L1) protein. Recent findings indicate that tumor mutational burden (TMB) is a unique feature that may improve response prediction to ICIs across multiple cancer types [1]. Nevertheless, only a minority of NSCLC patients will benefit from ICIs. Therefore, unraveling the genomics of NSCLC and the subsequent discovery of novel predictive biomarkers remains a high unmet need. Whole-genome sequencing (WGS) bounded with AI may identify biomarkers and composed signatures which will better than TMB or PD-L1 predict response to ICIs. Methods: To develop the PD1Dx classifier with the highest predictive value for ICI response, we combined WGS data analyses with machine learning approaches. Consistently, we divided WGS data of 57 NSCLCs derived from the Hartwig Medical Foundation (HMF) database into training (n = 39) and hold-out (n = 18) sets. Patients treated with pembrolizumab or nivolumab alone were labeled based solely on clinical metadata provided by the repository, reaching a total of 22 responders and 35 non-responders. Results: Recursive Feature Elimination using SHAP importance (ShapRFECV) selected 15 top predictive genomic features, based on which the final random forest model was built. The random forest model achieved the best performance, with an accuracy of 0.72, a recall of 0.73, and a precision of 0.80. Using the same learning method and dataset, we built a model based on a single TMB feature whose performance determined by accuracy, recall and precision was 0.67, 0.64, and 0.78, respectively. Apart from TMB, we also identified other predictive features, among the 15 top of which were, e.g., features related to transcriptional strand bias and C &gt; A/T single nucleotide variants correlating with mismatch repair. Conclusions: Our results confirm the predictive value of features other than TMB alone in predicting ICI responses in NSCLC. Further investigation is required to validate biomarkers of sensitivity and resistance to ICIs. Krieger T, Pearson I, Bell J, Doherty J, Robbins P. Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment. Diagn Pathol 2020;15:6.